Biaryl substituted triazoles as sodium channel blockers

ABSTRACT

Biaryl substituted triazole compounds represented by Formula I, II or III, or pharmaceutically acceptable salts thereof, and a process for making such compounds and salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, epilepsy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, and bipolar disorder, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier.

FIELD OF THE INVENTION

The present invention is directed to a series of biaryl substitutedtriazole compounds. In particular, this invention is directed to biarylsubstituted triazoles that are sodium channel blockers useful for thetreatment of chronic and neuropathic pain. The compounds of the presentinvention are also useful for the treatment of other conditions,including disorders of the central nervous system (CNS) such asepilepsy, manic depression, bipolar disorder, depression, anxiety anddiabetic neuropathy.

BACKGROUND OF THE INVENTION

Voltage-gated ion channels allow electrically excitable cells togenerate and propagate action potentials and therefore are crucial fornerve and muscle function. Sodium channels play a special role bymediating rapid depolarization, which constitutes the rising phase ofthe action potential and in turn activates voltage-gated calcium andpotassium channels. Voltage-gated sodium channels represent a multigenefamily. Nine sodium channel subtypes have been cloned and functionallyexpressed to date. [Clare, J. J., Tate, S, N., Nobbs, M. & Romanos, M.A. Voltage-gated sodium channels as therapeutic targets. Drug DiscoveryToday 5, 506-520 (2000)]. They are differentially expressed throughoutmuscle and nerve tissues and show distinct biophysical properties. Allvoltage-gated sodium channels are characterized by a high degree ofselectivity for sodium over other ions and by their voltage-dependentgating. [Catterall, W. A. Structure and function of voltage-gated sodiumand calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)].At negative or hyperpolarized membrane potentials, sodium channels areclosed. Following membrane depolarization, sodium channels open rapidlyand then inactivate. Sodium channels only conduct currents in the openstate and, once inactivated, have to return to the resting state,favored by membrane hyperpolarization, before they can reopen. Differentsodium channel subtypes vary in the voltage range over which theyactivate and inactivate as well as in their activation and inactivationkinetics.

Sodium channels are the target of a diverse array of pharmacologicalagents, including neurotoxins, antiarrhythmics, anticonvulsants andlocal anesthetics. [Clare, J. J., Tate, S, N., Nobbs, M. & Romanos, M.A. Voltage-gated sodium channels as therapeutic targets. Drug DiscoveryToday 5, 506-520 (2000)]. Several regions in the sodium channelsecondary structure are involved in interactions with these blockers andmost are highly conserved. Indeed, most sodium channel blockers known todate interact with similar potency with all channel subtypes.Nevertheless, it has been possible to produce sodium channel blockerswith therapeutic selectivity and a sufficient therapeutic window for thetreatment of epilepsy (e.g. lamotrigine, phenyloin and carbamazepine)and certain cardiac arrhythmias (e.g. lignocaine, tocamide andmexiletine).

It is well known that the voltage-gated Na⁺ channels in nerves play acritical role in neuropathic pain. Injuries of the peripheral nervoussystem often result in neuropathic pain persisting long after theinitial injury resolves. Examples of neuropathic pain include, but arenot limited to, postherpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, pain resultingfrom cancer and chemotherapy, chronic pelvic pain, complex regional painsyndrome and related neuralgias. It has been shown in human patients aswell as in animal models of neuropathic pain, that damage to primaryafferent sensory neurons can lead to neuroma formation and spontaneousactivity, as well as evoked activity in response to normally innocuousstimuli. [Carter, G. T. and B. S. Galer, Advances in the management ofneuropathic pain. Physical Medicine and Rehabilitation Clinics of NorthAmerica, 2001. 12(2): p. 447-459]. The ectopic activity of normallysilent sensory neurons is thought to contribute to the generation andmaintenance of neuropathic pain. Neuropathic pain is generally assumedto be associated with an increase in sodium channel activity in theinjured nerve. [Baker, M. D. and J. N. Wood, Involvement of Na channelsin pain pathways. TRENDS in Pharmacological Sciences, 2001. 22(1): p.27-31].

Indeed, in rat models of peripheral nerve injury, ectopic activity inthe injured nerve corresponds to the behavioral signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviorand motor function. [Mao, J. and L. L. Chen, Systemic lidocaine forneuropathic pain relief. Pain, 2000. 87: p. 7-17]. These effectiveconcentrations were similar to concentrations shown to be clinicallyefficacious in humans. [Tanelian, D. L. and W. G. Brose, Neuropathicpain can be relieved by drugs that are use-dependent sodium channelblockers: lidocaine, carbamazepine and mexiletine. Anesthesiology, 1991.74(5): p. 949-951]. In a placebo-controlled study, continuous infusionof lidocaine caused reduced pain scores in patients with peripheralnerve injury, and in a separate study, intravenous lidocaine reducedpain intensity associated with postherpetic neuralgia (PHN). [Mao, J.and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain,2000. 87: p. 7-17. Anger, T., et al., Medicinal chemistry of neuronalvoltage-gated sodium channel blockers. Journal of Medicinal Chemistry,2001. 44(2): p. 115-137]. Lidoderm®, lidocaine applied in the form of adermal patch, is currently the only FDA approved treatment for PHN.[Devers, A. and B. S. Galer, Topical lidocaine patch relieves a varietyof neuropathic pain conditions: an open-label study. Clinical Journal ofPain, 2000. 16(3): p. 205-208].

In addition to neuropathic pain, sodium channel blockers have clinicaluses in the treatment of epilepsy and cardiac arrhythmias. Recentevidence from animal models suggests that sodium channel blockers mayalso be useful for neuroprotection under ischaemic conditions caused bystroke or neural trauma and in patients with multiple sclerosis (MS).[Clare, J. J., et al. And Anger, T., et al.].

International Patent Publication WO 00/57877 describes aryl substitutedpyrazoles, imidazoles, oxazoles, thiazoles, and pyrroles and their usesas sodium channel blockers. International Patent Publication WO 01/68612describes aryl substituted pyridines, pyrimidines, pyrazines andtriazines and their uses as sodium channel blockers. InternationalPatent Publication WO 99/32462 describes triazine compounds for thetreatment for CNS disorders. However, there remains a need for novelcompounds and compositions that therapeutically block neuronal sodiumchannels with less side effects and higher potency than currently knowncompounds.

SUMMARY OF THE INVENTION

The present invention is directed to biaryl substituted triazolecompounds which are sodium channel blockers useful for the treatment ofchronic and neuropathic pain. The compounds of the present invention arealso useful for the treatment of other conditions, including disordersof the CNS such as epilepsy, manic depression and bipolar disorder. Thisinvention also provides pharmaceutical compositions comprising acompound of the present invention, either alone, or in combination withone or more therapeutically active compounds, and a pharmaceuticallyacceptable carrier.

This invention further comprises methods for the treatment of acutepain, chronic pain, visceral pain, inflammatory pain, neuropathic painand disorders of the CNS including, but not limited to, epilepsy, manicdepression, depression, anxiety and bipolar disorder comprisingadministering the compounds and pharmaceutical compositions of thepresent invention. The invention also encompasses a process for makingthe instant compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds represented by Formula (I) or(II):

or pharmaceutically acceptable salts thereof, wherein

R¹ is

-   (a) H;-   (b) C₁-C₆-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-cycloalkyl, or    C₁-C₄-alkyl-[C₃-C₆-cycloalkyl], any of which is optionally    substituted with one or more of the following substituents: F, CF₃,    OH, O—(C₁-C₄)alkyl, S(O)₀₋₂—(C₁-C₄)alkyl, O—CONR^(a)R^(b),    NR^(a)R^(b), N(R^(a))CONR^(a)R^(b), COO—(C₁-C₄)alkyl, COOH, CN,    CONR^(a)R^(b), SO₂NR^(a)R^(b), N(R^(a))SO₂NR^(a)R^(b), —C(═NH)NH₂,    tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl,    isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl,    pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl or piperazinyl;-   (c) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   (d) NO₂;-   (e) NR^(a)R^(b), —N(COR^(a))R^(b), —N(SO₂R^(a))R^(b),    —N(R^(a))SO₂R^(a), —N(OR^(a))CONR^(a)R^(b), —N(R^(a))CON(R^(a))₂, or    —N(R^(a))SO₂N(R^(a))₂;-   (f) —CH(OR^(a))R^(a), —C(OR^(b))CF₃, —CH(NR^(a))R^(a), C(═O)R^(a),    C(═O)CF₃, —SOCH₃, —SO₂CH₃, COOR^(a), CN, CONR^(a)R^(b),    —COCONR^(a)R^(b), —SO₂NR^(a)R^(b), —CH₂O—SO₂NR^(a)R^(b),    SO₂N(R^(a))OR^(a), —C(═NH)NH₂, CR^(a)═N—OR^(a), CH═CHCONR^(a)R^(b);-   (g) —CONR^(a)(CH₂)₀₋₂C(R^(a))(R^(b))(CH₂)₀₋₂CONR^(a)R^(b);-   (h) tetrazolyl, tetrazolinonyl, triazolyl, triazolinonyl,    imidazolyl, imidozolonyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, furyl, thienyl, pyrazolyl, pyrazolonyl, pyrrolyl,    pyridyl, pyrimidinyl, pyrazinyl, or phenyl, any of which is    optionally substituted with 1-3 independent substituents selected    from i) F, Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)R^(a), v)    C₁-C₆-alkyl, vi) —O—R^(a), vii) —NR^(a)R^(b), viii) —C₀-C₄-alkyl    —CO—OR^(a), ix) —(C₀-C₄-alkyl)-NH—CO—OR^(a), x)    —(C₀-C₄-alkyl)-CO—NR^(a)R^(b), xi) —S(O)₀₋₂R^(a), xii)    —SO₂NR^(a)R^(b), xiii) —NHSO₂R^(a), xiv) —C₁-C₄-perfluoroalkyl,    and xv) —O—C₁-C₄-perfluoroalkyl;-   (i) —C(R^(a))═C(R^(b))—COOR^(a), or    —C(R^(a))═C(R^(b))—CONR^(a)R^(b);

-   (k) piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, piperazin-1-yl    or 4-substituted piperazin-1-yl, any of which is optionally    substituted with 1-3 substituents selected from i) —CN, ii)    —C(═O)(R^(a)), iii) C₁-C₆-alkyl, iv) —OR^(a), v) —NR^(a)R^(b), vi)    —C₀-C₄-alkyl-CO—OR^(a), vii) —(C₀-C₄-alkyl)-NH—CO—OR^(a), viii)    —(C₀-C₄-alkyl)-CON(R^(a))(R^(b)), ix) —SR^(a), x) —S(O)₀₋₂R^(a), xi)    —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a) xiii)    —C₁-C₄-perfluoroalkyl and xiv) —O—C₁-C₄-perfluoroalkyl;

R^(a) is

-   (a) H;-   (b) C₁-C₄-alkyl, optionally substituted with one or more of the    following substituents: F, CF₃, OH, O—(C₁-C₄)alkyl,    S(O)₀₋₂—(C₁-C₄)alkyl, —OCONH₂, —OCONH(C₁-C₄alkyl),    —OCON(C₁-C₄alkyl)(C₁-C₄alkyl), —OCONHC₁-C₄alkyl-aryl),    —OCON(C₁-C₄alkyl)(C₁-C₄alkyl-aryl), NH₂, NH(C₁-C₄alkyl),    N(C₁-C₄alkyl)(C₁-C₄alkyl), NH(C₁-C₄alkyl-aryl),    N(C₁-C₄alkyl)(C₁-C₄alkyl-aryl), NHCONH₂, NHCONH(C₁-C₄alkyl),    NHCONH(C₁-C₄alkyl-aryl), —NHCON(C₁-C₄alkyl)(C₁-C₄alkyl),    NHCON(C₁-C₄alkyl)(C₁-C₄alkyl-aryl),    N(C₁-C₄alkyl)CON(C₁-C₄alkyl)(C₁-C₄alkyl),    N(C₁-C₄alkyl)CON(C₁-C₄alkyl)(C₁-C₄alkyl-aryl), COO—(C₁-C₄-alkyl),    COOH, CN, CONH₂, CONH(C₁-C₄alkyl), CON(C₁-C₄alkyl)(C₁-C₄alkyl),    SO₂NH₂, SO₂NH(C₁-C₄alkyl), SO₂NH(C₁-C₄alkyl-aryl),    SO₂N(C₁-C₄alkyl)(C₁-C₄alkyl), NHSO₂NH₂, —C(═NH)NH₂, tetrazolyl,    triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl,    pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl or piperazinyl;-   (c) C₀-C₄-alkyl-(C₁-C₄)-perfluoroalkyl; or-   (d) —C₁-C₄-alkyl-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl,    furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl,    isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is    optionally substituted with 1-3 substituents selected from i) F, Cl,    Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(C₁-C₄-alkyl), v)    —O(C₁-C₄-alkyl), vi) —N(C₁-C₄-alkyl)(C₁-C₄-alkyl), vii) —C₁₋₁₀alkyl,    and viii) —C₁₋₁₀alkyl, wherein one or more of the alkyl carbons can    be replaced by a —O—, —S(O)₁₋₂—, —O—C(O)—, —C(O)—O—, —C(O)—,    —CH(OH)—, —C═C—, or —C≡C—;

R^(b) is

-   (a) H; or-   (b) C₁-C₆-alkyl, optionally substituted with one or more of the    following substituents: F, CF₃, OH, O—(C₁-C₄)alkyl,    S(O)₀₋₂—(C₁-C₄)alkyl, —OCONH₂, —OCONH(C₁-C₄alkyl), NH₂,    NH(C₁-C₄alkyl), N(C₁-C₄alkyl)(C₁-C₄alkyl), NHCONH₂,    NHCONH(C₁-C₄alkyl), —NHCON(C₁-C₄alkyl)(C₁-C₄alkyl),    COO—(C₁-C₄-alkyl), COOH, CN, or CONH₂;

R² is:

-   (a) H;-   (b) —C₁-C₄-alkyl, —C₃-C₆-cycloalkyl or    —C₁-C₄-alkyl-(C₃-C₆)-cycloalkyl, optionally substituted with one or    more of the following substituents: F, CF₃, OH, O—(C₁-C₄)alkyl,    S(O)₀₋₂—(C₁-C₄)alkyl, O—CONR^(a)R^(b), NR^(a)R^(b),    N(R^(a))CONR^(a)R^(b), COO—(C₁-C₄)alkyl, COOH, CN, CONR^(a)R^(b),    SO₂NR^(a)R^(b), N(R^(a)R^(b))SO₂NR^(a)R^(b), —C(═NH)NH₂, tetrazolyl,    triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl,    pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl or piperazinyl;-   (c) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   (d) aryl or —(C₁-C₄-alkyl)-aryl, wherein aryl is phenyl, pyridyl,    pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl,    thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which    is optionally substituted with 1-3 substituents selected from i) F,    Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(R^(a)), v) —OR^(a), vi)    —NR^(a)R^(b), vii) —C₀₋₄alkyl-CO—OR^(a), viii)    —(C₀₋₄alkyl)-NH—CO—OR^(a), ix) —(C₀₋₄alkyl)-CO—N(R^(a))(R^(b)), x)    —S(O)₀₋₂R^(a), xi) —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a), xiii)    —C₁₋₁₀alkyl, and xiv) —C₁₋₁₀alkyl, wherein one or more of the alkyl    carbons can be replaced by a —NR^(a)—, —O—, —S(O)₁₋₂—, —O—C(O)—,    —C(O)—O—, —C(O)—N(R^(a))—, —N(R^(a))—C(O)—,    —N(R^(a))—C(O)—N(R^(a))—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;-   (e) —C(═O)(R⁸), —CONR^(a)R^(b), —COO—(C₁-C₄)alkyl, —SO₂R^(a),    —SO₂N(R^(a))(R^(b));    R³ and R⁴ each independently is:-   (a) H;-   (b) —C₁-C₆-alkyl, —C₂-C₆-alkenyl, —C₂-C₆-alkynyl or    —C₃-C₆-cycloalkyl, any of which is optionally substituted with one    or more of the following substituents: F, CF₃, —O—(C₁-C₄)alkyl, CN,    —N(R^(a))(R^(b)), —N(R^(a))CO—(C₁-C₄)alkyl, COOR^(b),    CON(R^(a))(R^(b)) or phenyl;-   (c) —O—C₀-C₆-alkyl, —O-aryl, or —O—C₁-C₄-alkyl-aryl, wherein aryl is    phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl,    pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl    of which is optionally substituted with 1-3 substituents selected    from i) F, Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(R^(a)), v)    —OR^(a), vi) —NR^(a)R^(b), vii) —C₀₋₄alkyl-CO—OR^(a), viii)    —(C₀₋₄alkyl)-NH—CO—OR^(a), ix) —(C₀₋₄alkyl)-CO—N(R^(a))(R^(b)), x)    —S(O)₀₋₂R^(a), xi) —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a), xiii)    —C₁₋₁₀alkyl, and xiv) —C₁₋₁₀alkyl, wherein one or more of the alkyl    carbons can be replaced by a —NR^(a)—, —O—, —S(O)₁₋₂—, —O—C(O)—,    —C(O)—O—, —C(O)—N(R^(a))—, —N(R^(a))—C(O)—,    —N(R^(a))—C(O)—N(R^(a))—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;-   (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, or    —O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl; or-   (e) CN, NH₂, NO₂, F, Cl, Br, I, OH, OCON(R^(a))(R^(b))    O(C₁-C₄-alkyl)CONR^(a)R^(b), —OSO₂N(R^(a))(R^(b)), COOR^(b),    CON(R^(a))(R^(b)), or aryl, wherein aryl is phenyl, pyridyl,    pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl,    thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which    is optionally substituted with 1-3 substituents selected from i) F,    Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(R^(a)), v) —OR^(a), vi)    —NR^(a)R^(b), vii) —C₀₋₄alkyl-CO—OR^(a), viii)    —(C₀₋₄alkyl)-NH—CO—OR^(a), ix) —(C₀₋₄alkyl)-CO—N(R^(a))(R^(b)), x)    —S(O)₀₋₂R^(a), xi) —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a), xiii)    —C₁₋₁₀alkyl, and xiv) —C₁₋₁₀alkyl, wherein one or more of the alkyl    carbons can be replaced by a —NR^(a)—, —O—, —S(O)₁₋₂—, —O—C(O)—,    —C(O)—O—, —C(O)—N(R^(a))—, —N(R^(a))—C(O)—,    —N(R^(a))—C(O)—N(R^(a))—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C; and    R⁵, R⁶ and R⁷ each independently is:-   (a) H;-   (b) C₁-C₆-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₃-C₆-cycloalkyl,    any of which is optionally substituted with one or more of the    following substituents: F, CF₃, OH, O—(C₁-C₄)alkyl, OCON(R^(a))(R ),    NR^(a)R^(b), COOR^(a), CN, CONR^(a)R^(b),    N(R^(a)R^(b))CONR^(a)R^(b), N(R^(a)R^(b))SO₂NR^(a)R^(b),    SO₂NR^(a)R^(b), S(O)₀₋₂(C₁-C₄-alkyl), —C(═NH)NH₂, tetrazolyl,    triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl,    thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl,    pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl, or piperazinyl;-   (c) —O—C₁-C₆-alkyl, —O—C₃-C₆-cycloalkyl, —S—C₁-C₆-alkyl or    —S—C₃-C₆-cycloalkyl, any of which is optionally substituted with one    or more of the following substituents: F, CF₃, OH, O—(C₁-C₄)alkyl,    NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, COOH, CN, CONH₂,    CONH(C₁-C₄-alkyl), CONH(C₁-C₄-alkyl)₂, SO₂NH₂, SO₂NH(C₁-C₄-alkyl),    tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl,    isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl,    pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl,    pyrrolidinyl, or piperazinyl;-   (d) —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, or    —O—C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl;-   (e) —O-aryl, or —O—C₁-C₄-alkyl-aryl, wherein aryl is phenyl,    pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl,    pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl    of which is optionally substituted with 1-3 substituents selected    from i) F, Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(R^(a)), v)    —OR^(a), vi) —NR^(a)R^(b), vii) —C₀₋₄alkyl-CO—OR^(a), viii)    —(C₀₋₄-alkyl)-NH—CO—, ix) —(C₀₋₄alkyl)-CO—N(R^(a))(R^(b)), x)    —S(O)₀₋₂R^(a), xi) —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a), xiii)    —C₁₋₁₀alkyl, and xiv) —C₁₋₁₀alkyl, wherein one or more of the alkyl    carbons can be replaced by a —NR^(a)—, —O—, —S(O)₁₋₂—, —O—C(O)—,    —C(O)—O—, —C(O)—N(R^(a))—, —N(R^(a))C(O)—, —N(R^(a))—C(O)—N(R^(a))—,    —C(O)—, —CH(OH)—, —C═C—, or —C≡C;-   (f) CN, N(R^(a))(R^(b)), NO₂, F, Cl, Br, I, —OR^(a), —SR^(a),    —OCON(R^(a))(R^(b)), —OSO₂N(R^(a))(R^(b)), COOR^(b),    CON(R^(a))(R^(b)), —N(R^(a))CON(R^(a))(R^(b)),    —N(R^(a))SO₂N(R^(a))(R^(b)), C(OR^(b))R^(a), C(OR^(a))CF₃,    C(NHR^(a))CF₃, C(═O)R^(a), C(═O)CF₃, —SOCH₃, —SO₂CH₃,    —NHSO₂(C₁₋₆-alkyl), —NHSO₂-aryl, SO₂N(R^(a))(R^(b)),    —CH₂OSO₂N(R^(a))(R^(b)), SO₂N(R^(b))—OR^(a), —C(═NH)NH₂,    —CR^(a)═N—OR^(a), CH═CH or aryl, wherein aryl is phenyl, pyridyl,    pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl,    thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which    is optionally substituted with 1-3 substituents selected from i) F,    Cl, Br, I, ii) —CN, iii) —NO₂, iv) —C(═O)(R^(a)), v) —OR, vi)    —NR^(a)R^(b), vii) —C₀₋₄alkyl-CO—OR^(a), viii)    —(C₀₋₄alkyl)-NH—CO—OR^(a), ix) —(C₀₋₄alkyl)-CO—N(R^(a))(R^(b)), x)    —S(O)₀₋₂R^(a), xi) —SO₂N(R^(a))(R^(b)), xii) —NR^(a)SO₂R^(a), xiii)    —C₁₋₁₀alkyl, and xiv) —C₁₋₁₀alkyl, wherein one or more of the alkyl    carbons can be replaced by a —NR^(a)—, —O—, —S(O)₁₋₂—, —O—C(O)—,    —C(O)—O—, —C(O)—N(R^(a))—, —N(R^(a))—C(O)—,    —N(R^(a))—C(O)—N(R^(a))—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C;

with the proviso that when R⁵ and R⁶ are present on adjacent carbonatoms, R⁵ and R⁶, together with the benzene ring to which they areattached, may form a bicyclic aromatic ring selected from naphthyl,indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzofuryl,benzothienyl, benzoxazolyl, benzothiazolyl, and benzimidazolyl, any ofwhich is optionally substituted with 1-4 independent substituentsselected from i) halogen, ii) —CN, iii) —NO₂, iv) —CHO, v) —O—C₁₋₄alkyl,vi) —N(C₀₋₄alkyl)(C₀₋₄alkyl), vii) —C₀₋₄alkyl-CO—O(C₀₋₄alkyl), viii)—(C₀₋₄alkyl)-NH—CO—O(C₀₋₄alkyl), ix)—(C₀₋₄alkyl)-CO—N(C₀₋₄alkyl)(C₀₋₄alkyl), x) —S(C₀₋₄alkyl), xi)—S(O)(C₁₋₄alkyl), xii) —SO₂(C₀₋₄alkyl), xiii)—SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), xiv) —NHSO₂(C₀₋₄alkyl)(C₀₋₄alkyl), xv)—C₁₋₁₀alkyl, and xvi) —C₁₋₁₀alkyl in which one or more of the carbonscan be replaced by a —N(C₀₋₆alkyl)-, —O—, —S(O)₁₋₂—, —O—C(O)—, —C(O)—O—,—C(O)—N(C₀₋₆alkyl)-, —N(C₀₋₆alkyl)-C(O)—,—N(C₀₋₆alkyl)-C(O)—N(C₀₋₆alkyl)-, —C(O)—, —CH(OH), —C═C—, or —C≡C—.

The present invention further comprises compounds described by FormulaIII:

or pharmaceutical salts thereof, whereinR¹-R⁷ each is as defined above.

In one aspect, the present invention provides a compound described bythe chemical Formula (I), or a pharmaceutically acceptable salt thereof,wherein

R⁵ is other than H and is attached at the ortho position, and all othervariables are as previously defined.

In an embodiment of this first aspect, the present invention provides acompound described by the chemical Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein

R⁵ is —OR^(a), and all other variables are as previously defined.

In another embodiment of this first aspect, the present inventionprovides a compound described by the chemical Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is optionally substituted C₁-C₆-alkyl, optionally substitutedC₃-C₆-cycloalkyl, —C(═O)R^(a) or CONR^(a)R^(b), and all other variablesare as previously defined.

In a second aspect, the present invention provides a compound describedby the chemical Formula (II), or a pharmaceutically acceptable saltthereof, wherein

R⁵ is other than H and is attached at the ortho position, and all othervariables are as previously defined.

In an embodiment of this second aspect, the present invention provides acompound described by the chemical Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein

R⁵ is —OR^(a), and all other variables are as previously defined.

In another embodiment of this second aspect, the present inventionprovides a compound described by the chemical Formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is optionally substituted C₁-C₆-alkyl, optionally substitutedC₃-C₆-cycloalkyl, —C(═O)R^(a) or CONR^(a)R^(b), and all other variablesare as previously defined.

In a third aspect, the present invention provides a compound describedby the chemical Formula (III), or a pharmaceutically acceptable saltthereof, wherein

R⁵ is other than H and is attached at the ortho position, and all othervariables are as previously defined.

In an embodiment of this third aspect, the present invention provides acompound described by the chemical Formula (III), or a pharmaceuticallyacceptable salt thereof, wherein

R⁵ is —OR^(a), and all other variables are as previously defined.

In another embodiment of this third aspect, the present inventionprovides a compound described by the chemical Formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is optionally substituted C₁-C₆-alkyl, optionally substitutedC₃-C₆-cycloalkyl, —C(═O)R^(a) or CONR^(a)R^(b), and all other variablesare as previously defined.

In a fourth aspect, the present invention provides compounds describedby the chemical Formula (I), which includes compounds of the Formula Ia:

or pharmaceutically acceptable salts thereof, wherein

R¹ is optionally substituted C₁-C₆-alkyl, optionally substitutedC₃-C₆-cycloalkyl, —C(═O)R^(a) or CONR^(a)R^(b),

R⁵ is —OR^(a) or —C₀-C₄-alkyl-C₁-C₄-perfluoroalkyl, and all othervariables are as previously defined.

The present invention further provides a process for making a compoundof Formula (I), or a pharmaceutically acceptable salt thereof,

the process comprising reacting a compound of Formula 34 or 35:

with a compound of Formula 36:

wherein R¹-R⁷ each is as defined above, in the presence of a base toyield a compound of Formula (I),or a pharmaceutically acceptable salt thereof.

In a first aspect of the inventive process, the present inventionprovides a process for making a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is H, <(═O)R^(a), COOR^(a), CONR^(a)R^(b), C₁-C₆ alkyl or C₃-C₆cycloalkyl, wherein alkyl and cycloalkyl is optionally substituted withone or more of F, OH, or NR^(a)R^(b),

R² is H,

R⁵, R⁶ and R⁷ each independently is H, F, —OR^(a), C₁-C₆-alkyl, or—O—C₁-C₆-alkyl, optionally substituted with one or more of F, CF₃, orO—(C₁-C₄)alky, and all other variables are as previously defined.

In a second aspect of the inventive process, the present inventionprovides a process for making a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

the base is a metal acetate, metal carbonate or tertiary amine.

In a third aspect of the inventive process, the present inventionprovides a process for making a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

the base is potassium acetate.

The present invention further provides a process for making a compoundof Formula (I), or a pharmaceutically acceptable salt thereof,

the process comprising reacting a compound of Formula 34 or 35:

with a compound of Formula 36:

wherein R¹-R² each is as defined above, in the presence of a base, andoptionally an alcoholic solvent, and optionally heat, to yield acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl meanscarbon chains which may be linear or branched or combinations thereof.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl. “Alkenyl,”“alkynyl” and other like terms include carbon chains containing at leastone unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, and1,2,3,4-tetrahydronaphalene. Similarly, “cycloalkenyl” means carbocyclescontaining no heteroatoms and at least one non-aromatic C—C double bond,and include mono-, bi- and tricyclic partially saturated carbocycles, aswell as benzofused cycloalkenes. Examples of cycloalkenyl includecyclohexenyl, and indenyl. The term “aryl” includes, but is not limitedto, an aromatic substituent that is a single ring or multiple ringsfused together. When formed of multiple rings, at least one of theconstituent rings is aromatic. The term “aryl”, unless specificallynoted otherwise, also includes heteroaryls, and thus includes stable 5-to 7-membered monocyclic and stable 9- to 10-membered fused bicyclicheterocyclic ring systems that consist of carbon atoms and from one tofour heteroatoms selected from the group consisting of N, O and S,wherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized. Suitable arylgroups include phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl,pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, andoxadiazolyl.

The term “cycloalkyloxy,” unless specifically stated otherwise, includesa cycloalkyl group connected by a short C₁₋₂alkyl to the oxy connectingatom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminal group and is a direct bond whenthe alkyl is a bridging group.

The term “hetero,” unless specifically stated otherwise, includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five-memberring containing from 4 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, andtetrazolyl. Examples of heterocycloalkyls include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or nocarbon atoms. However, at least one heteroatom must be present. Thus, asan example, a heteroC₀₋₄alkyl having no carbon atoms but one N atomwould be a —NH— if a bridging group and a —NH₂ if a terminal group.Analogous bridging or terminal groups are clear for an O or Sheteroatom.

The term “amine,” unless specifically stated otherwise, includesprimary, secondary and tertiary amines.

The term “carbonyl,” unless specifically stated otherwise, includes aC₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the alkyl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

As used herein for purposes of the inventive process, the term “base”includes metal acetate bases, metal carbonate bases, and tertiary aminebases. Examples of metal acetate bases include potassium acetate andsodium acetate. Examples of metal carbonate bases include potassiumcarbonate and sodium carbonate. Tertiary amine bases include trialkylamine bases such as triethylamine.

As used herein for purposes of the inventive process, the term“alcoholic solvent” or “alcohol solvent” includes, for example,methanol, ethanol, isopropanol and 1-butanol.

Where the inventive process utilizes heat, the process can be carriedout in the temperature range of between about 40° C. to about 150° C.,including about 50° C. to about 140° C., about 50° C. to about 130° C.,about 60° C. to about 120° C., about 65° C. to about 100° C., or about65° C. to about 85° C.

As used herein, the term “solvent/co-solvent mixture” includes solventmixtures such as toluene/tetrahydrofuran, tetrahydrofuran/diethylether,toluene/diethylether, tetrahydrofuran/methyl-t-butylether,toluene/methyl-t-butylether, toluene/dioxane, andtetrahydrofuran/dioxane.

Compounds described herein may contain one or more double bonds and maythus give rise to cis/trans isomers as well as other conformationalisomers. The present invention includes all such possible isomers aswell as mixtures of such isomers unless specifically stated otherwise.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereoisomers and optical isomers. Thepresent invention includes all such possible diastereoisomers as well astheir racemic mixtures, their substantially pure resolved enantiomers,all possible geometric isomers, and pharmaceutically acceptable saltsthereof. The above chemical Formulas are shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of the chemical Formulas and pharmaceutically acceptablesalts thereof. Further, mixtures of stereoisomers as well as isolatedspecific stereoisomers are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, as well as cyclic amines andsubstituted amines such as naturally occurring and synthesizedsubstituted amines. Other pharmaceutically acceptable organic non-toxicbases from which salts can be formed include ion exchange resins suchas, for example, arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, andtromethamine.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Suchadditional therapeutic agents can include, for example, i) opiateagonists or antagonists, ii) calcium channel antagonists, iii) 5HTreceptor agonists or antagonists, iv) sodium channel antagonists, v)NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors,vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs(“NSAID”), ix) selective serotonin reuptake inhibitors (“SSRI”) and/orselective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x)tricyclic antidepressant drugs, xi) norepinephrine modulators, xii)lithium, xiii) valproate, and xiv) neurontin (gabapentin). The instantcompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

The present compounds and compositions are useful for the treatment ofchronic, visceral, inflammatory and neuropathic pain syndromes. They areuseful for the treatment of pain resulting from traumatic nerve injury,nerve compression or entrapment, postherpetic neuralgia, trigeminalneuralgia, and diabetic neuropathy. The present compounds andcompositions are also useful for the treatment of chronic lower backpain, phantom limb pain, chronic pelvic pain, neuroma pain, complexregional pain syndrome, chronic arthritic pain and related neuralgias,and pain associated with cancer, chemotherapy, HIV and HIVtreatment-induced neuropathy. Compounds of this invention may also beutilized as local anesthetics. Compounds of this invention are usefulfor the treatment of irritable bowel syndrome and related disorders, aswell as Crohns disease.

The instant compounds have clinical uses for the treatment of epilepsyand partial and generalized tonic seizures. They are also useful forneuroprotection under ischaemic conditions caused by stroke or neuraltrauma and for treating multiple sclerosis. The present compounds areuseful for the treatment of tachy-arrhythmias. Additionally, the instantcompounds are useful for the treatment of neuropsychiatric disorders,including mood disorders, such as depression or more particularlydepressive disorders, for example, single episodic or recurrent majordepressive disorders and dysthymic disorders, or bipolar disorders, forexample, bipolar I disorder, bipolar II disorder and cyclothymicdisorder; anxiety disorders, such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders;

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents, such as norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), □-adrenoreceptor antagonists, atypical anti-depressants,benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A)partial agonists, neurokinin-1 receptor antagonists, corticotropinreleasing factor (CRF) antagonists, and pharmaceutically acceptablesalts thereof.

Further, it is understood that compounds of this invention can beadministered at prophylactically effective dosage levels to prevent theabove-recited conditions and disorders, as well as to prevent otherconditions and disorders associated with sodium channel activity.

Creams, ointments, jellies, solutions, or suspensions containing theinstant compounds can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of inflammatory and neuropathicpain, or alternatively about 0.5 mg to about 7 g per patient per day.For example, inflammatory pain may be effectively treated by theadministration of from about 0.01 mg to about 75 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about3.5 g per patient per day. Neuropathic pain may be effectively treatedby the administration of from about 0.01 mg to about 125 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5 g per patient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Suchpatient-related factors include the age, body weight, general health,sex, and diet of the patient. Other factors include the time and routeof administration, rate of excretion, drug combination, and the severityof the particular disease undergoing therapy.

In practice, the compounds of the invention or pharmaceuticallyacceptable salts thereof, can be combined as the active ingredient inintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Thus,the pharmaceutical compositions of the present invention can bepresented as discrete units suitable for oral administration such ascapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient. Further, the compositions can be presented as apowder, as granules, as a solution, as a suspension in an aqueousliquid, as a non-aqueous liquid, as an oil-in-water emulsion or as awater-in-oil liquid emulsion. In addition to the common dosage forms setout above, the compounds of the invention or pharmaceutically acceptablesalts thereof, may also be administered by controlled release meansand/or delivery devices. The compositions may be prepared by any of themethods of pharmacy. In general, such methods include a step of bringinginto association the active ingredient with the carrier that constitutesone or more necessary ingredients. In general, the compositions areprepared by uniformly and intimately admixing the active ingredient withliquid carriers or finely divided solid carriers or both. The productcan then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the present compounds. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moretherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents can be used to form oral solidpreparations such as powders, capsules and tablets. Because of theirease of administration, tablets and capsules are the preferred oraldosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage, and thus should be preserved against the contaminating actionof microorganisms such as bacteria and fungi. The carrier can be asolvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, and dusting powder. Further, the compositions can bein a form suitable for use in transdermal devices. These formulationsmay be prepared, utilizing a compound of the instant invention, orpharmaceutically acceptable salts thereof, via conventional processingmethods. As an example, a cream or ointment is prepared by mixinghydrophilic material and water, together with about 5 wt % to about 10wt % of the compound, to produce a cream or ointment having a desiredconsistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid, such as, forexample, where the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, and preservatives (including anti-oxidants). Furthermore,other adjuvants can be included to render the formulation isotonic withthe blood of the intended recipient. Compositions containing a compoundof the present invention, or pharmaceutically acceptable salts thereof,can also be prepared in powder or liquid concentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to block sodium channels. Accordingly, an aspect of theinvention is the treatment in mammals of maladies that are amenable toamelioration through blockage of neuronal sodium channels, including,for example, acute pain, chronic pain, visceral pain, inflammatory pain,and neuropathic pain by administering an effective amount of a compoundof this invention. The term “mammals” includes humans, as well as otheranimals, such as, for example, dogs, cats, horses, pigs, and cattle.Accordingly, it is understood that the treatment of mammals other thanhumans refers to the treatment of clinical conditions in non-humanmammals that correlate to the above-recited conditions.

Further, as described above, the instant compounds can be utilized incombination with one or more therapeutically active compounds. Inparticular, the inventive compounds can be advantageously used incombination with i) opiate agonists or antagonists, ii) calcium channelantagonists, iii) 5HT receptor agonists or antagonists, iv) sodiumchannel antagonists, v) N-methyl-D-aspartate (NMDA) receptor agonists orantagonists, vi) COX-2 selective inhibitors, vii) neurokinin receptor 1(NK1) antagonists, viii) non-steroidal anti-inflammatory drugs (NSAID),ix) selective serotonin reuptake inhibitors (SSRI) and/or selectiveserotonin and norepinephrine reuptake inhibitors (SSNRI), x) tricyclicantidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii)valproate, and xiv) neurontin (gabapentin).

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise.

Ac Acetyl AIBN 2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol BnBenzyl CAMP cyclic adenosine-3′,5′-monophosphate DAST(diethylamino)sulfur trifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide Dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃NTriethylamine GST glutathione transferase HMDS Hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅•KHSO₄•K₂SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone) palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. or RT room temperature Rac.Racemic SAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene C₃H₅ Allyl

Alkyl Group Abbreviations

Me = Methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu =normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiarybutyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex =cyclohexyl

The following in vitro and in vivo assays were used in assessing thebiological activity of the instant compounds.

Compound Evaluation (In Vitro Assay):

The identification of inhibitors of the sodium channel is based on theability of sodium channels to cause cell depolarization when sodium ionspermeate through agonist-modified channels. In the absence ofinhibitors, exposure of an agonist-modified channel to sodium ions willcause cell depolarization. Sodium channel inhibitors will prevent celldepolarization caused by sodium ion movement through agonist-modifiedsodium channels. Changes in membrane potential can be determined withvoltage-sensitive fluorescence resonance energy transfer (FRET) dyepairs that use two components, a donor coumarin (CC₂DMPE) and anacceptor oxanol (DiSBAC₂(3)). Oxanol is a lipophilic anion anddistributes across the membrane according to membrane potential. In thepresence of a sodium channel agonist, but in the absence of sodium, theinside of the cell is negative with respect to the outside, oxanol isaccumulated at the outer leaflet of the membrane and excitation ofcoumarin will cause FRET to occur. Addition of sodium will causemembrane depolarization leading to redistribution of oxanol to theinside of the cell, and, as a consequence, to a decrease in FRET. Thus,the ratio change (donor/acceptor) increases after membranedepolarization. In the presence of a sodium channel inhibitor, celldepolarization will not occur, and therefore the distribution of oxanoland FRET will remain unchanged.

Cells stably transfected with the PN1 sodium channel (HEK-PN1) weregrown in polylysine-coated 96-well plates at a density of ca. 140,000cells/well. The media was aspirated, and the cells were washed with PBSbuffer, and incubated with 100 Ml of 10 Mm CC₂-DMPE in 0.02% pluronicacid. After incubation at 25° C. for 45 min, media was removed and cellswere washed 2× with buffer. Cells were incubated with 100 Ml ofDiSBAC₂(3) in TMA buffer containing 20 Mm veratridine, 20 Nmbrevetoxin-3, and test sample. After incubation at 25° C. for 45 min inthe dark, plates were placed in the VIPR instrument, and thefluorescence emission of both CC₂-DMPE and DiSBAC₂(3) recorded for 10 s.At this point, 100 Ml of saline buffer was added to the wells todetermine the extent of sodium-dependent cell depolarization, and thefluorescence emission of both dyes recorded for an additional 20 s. Theratio CC₂-DMPE/DiSBAC₂(3), before addition of saline buffer equals 1. Inthe absence of inhibitors, the ratio after addition of saline bufferis >1.5. When the sodium channel has been completely inhibited by eithera known standard or test compound, this ratio remains at 1. It ispossible, therefore, to titrate the activity of a sodium channelinhibitor by monitoring the concentration-dependent change influorescence ratio.

Electrophysiological Assays (In Vitro Assays):

Cell preparation: A HEK-293 cell line stably expressing the PN1 sodiumchannel subtype was established in-house. The cells were cultured in MEMgrowth media (Gibco) with 0.5 mg/Ml G418, 50 units/Ml Pen/Strep and 1 Mlheat-inactivated fetal bovine serum at 37° C. and 10% CO₂. Forelectrophysiological recordings, cells were plated on 35 mm dishescoated with poly-D-lysine.

Whole-cell recordings: HEK-293 cells stably expressing the PN1 sodiumchannel subtype were examined by whole cell voltage clamp (Hamill, etal. Pfluegers Archives 391:85-100 (1981)) using an EPC-9 amplifier andPulse software (HEKA Electronics, Lamprecht, Germany). Experiments wereperformed at room temperature. Electrodes were fire-polished toresistances of 2-4 MΩ. Voltage errors were minimized by seriesresistance compensation, and the capacitance artifact was canceled usingthe EPC-9's built-in circuitry. Data were acquired at 50 kHz andfiltered at 7-10 kHz. The bath solution consisted of 40 mM NaCl, 120 mMNMDG Cl, 1 mM KCl, 2.7 mM CaCl₂, 0.5 mM MgCl₂, 10 mM NMDG HEPES, Ph 7.4,and the internal (pipet) solution contained 110 mM Cs-methanesulfonate,5 mM NaCl, 20 mM CsCl, 10 mM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM CsHEPES, Ph 7.4.

The following protocols were used to estimate the steady-state affinityof compounds for the resting and inactivated state of the channel (K_(r)and K_(i), respectively):

1. 8 ms test-pulses to depolarizing voltages from 60 Mv to +50 Mv from aholding potential of −90 Mv were used to construct current-voltagerelationships (IV-curves). A voltage near the peak of the IV-curve(typically −10 or 0 Mv) was used as the test-pulse voltage throughoutthe remainder of the experiment.

2. Steady-state inactivation (availability) curves were constructed bymeasuring the current activated during an 8 ms test-pulse following 10 sconditioning pulses to potentials ranging from −120 Mv to −10 Mv.

3. Compounds were applied at a holding potential at which 20-50% of thechannels was inactivated and sodium channel blockage was monitoredduring 8 ms test pulses at 2 s intervals.

4. After the compounds equilibrated, the voltage-dependence ofsteady-state inactivation in the presence of compound was determinedaccording to protocol 2) above. Compounds that block the resting stateof the channel decrease the current elicited during test-pulses from allholding potentials, whereas compounds that primarily block theinactivated state shift the mid-point of the steady-state inactivationcurve. The maximum current at negative holding potentials (I_(max)) andthe difference in the mid-points of the steady-state inactivation curves(ΔV) in control and in the presence of a compound were used to calculateK_(r) and K_(i) using the following equations:

$K_{r} = \frac{\lbrack{Drug}\rbrack*I_{{Max},{Drug}}}{I_{{Max},{Control}} - I_{{Max},{Drug}}}$$K_{i} = \frac{\lbrack{Drug}\rbrack}{{\left( {1 + \frac{\lbrack{Drug}\rbrack}{K_{r}}} \right)*^{\frac{{- \Delta}\; V}{k}}} - 1}$

In cases where the compound did not affect the resting state, K_(i) wascalculated using the following equation:

$K_{i} = \frac{\lbrack{Drug}\rbrack}{^{\frac{{- \Delta}\; V}{k}} - 1}$

Rat Formalin Paw Test (In Vivo Assay):

Compounds were assessed for their ability to inhibit the behavioralresponse evoked by a 50 Ml injection of formalin (5%). A metal band wasaffixed to the left hind paw of male Sprague-Dawley rats (Charles River,200-250 g) and each rat was conditioned to the band for 60 min within aplastic cylinder (15 cm diameter). Rats were dosed with either vehicleor a test compound either before (local) or after (systemic) formalinchallenge. For local administration, compounds were prepared in a 1:4:5vehicle of ethanol, PEG400 and saline (EPEGS) and injectedsubcutaneously into the dorsal surface of the left hind paw 5 min priorto formalin. For systemic administration, compounds were prepared ineither a EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicleand were injected i.v. (via the lateral tail vein 15 min after formalin)or p.o. (60 min before formalin). The number of flinches was countedcontinuously for 60 min using an automated nociception analyzer (UCSDAnesthesiology Research, San Diego, Calif.). Statistical significancewas determined by comparing the total flinches detected in the early(0-10 min) and late (11-60 min) phase with an unpaired t-test.

In Vivo Assay Using Rat CFA Model:

Unilateral inflammation was induced with a 0.2 ml injection of completeFreund's adjuvant (CFA: Mycobacterium tuberculosis, Sigma; suspended inan oil/saline (1:1) emulsion; 0.5 mg Mycobacterium/Ml) in the plantarsurface of the left hindpaw. This dose of CFA produced significant hindpaw swelling but the animals exhibited normal grooming behavior andweight gain over the course of the experiment. Mechanical hyperalgesiawas assessed 3 days after tissue injury using a Randall-Selitto test.Repeated Measures ANOVA, followed by Dunnett's Post Hoc test.

SNL: Mechanical Allodynia (In Vivo Assay):

Tactile allodynia was assessed with calibrated von Frey filaments usingan up-down paradigm before and two weeks following nerve injury. Animalswere placed in plastic cages with a wire mesh floor and allowed toacclimate for 15 min before each test session. To determine the 50%response threshold, the von Frey filaments (over a range of intensitiesfrom 0.4 to 28.8 g) were applied to the mid-plantar surface for 8 s, oruntil a withdrawal response occurred. Following a positive response, anincrementally weaker stimulus was tested. If there was no response to astimulus, then an incrementally stronger stimulus was presented. Afterthe initial threshold crossing, this procedure was repeated for fourstimulus presentations per animal per test session. Mechanicalsensitivity was assessed 1 and 2 hr post oral administration of the testcompound.

The compounds described in this invention displayed sodium channelblocking activity of from about <0.1 mM to about <50 mM in the in vitroassays described above. It is advantageous that the compounds displaysodium channel blocking activity of <5 mM in the in vitro assays. It ismore advantageous that the compounds display sodium channel blockingactivity of <1 mM in the in vitro assays. It is even more advantageousthat the compounds display sodium channel blocking activity of <0.5 mMin the in vitro assays. It is still more advantageous that the compoundsdisplay sodium channel blocking activity of <0.1 mM in the in vitroassays.

The present compounds can be prepared according to the general Schemesprovided below as well as the procedures provided in the Examples. Thefollowing Schemes and Examples further describe, but do not limit, thescope of the invention.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions: All operations were carriedout at room or ambient temperature; that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. When given, yieldsare for illustration only. When given, NMR data is in the form of delta(6) values for major diagnostic protons, given in parts per million(ppm) relative to tetramethylsilane (TMS) as internal standard,determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.Conventional abbreviations used for signal shape are: s. singlet; d.doublet; t. triplet; m. multiplet; br. Broad; etc. In addition, “Ar”signifies an aromatic signal. Chemical symbols have their usualmeanings; the following abbreviations are used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), ml(milliliters), g (gram(s), mg (milligrams(s), mol (moles), mmol(millimoles), eq (equivalent(s).

Methods of Synthesis

Compounds of the present invention can be prepared according to theSchemes provided below as well as the procedures provided in theExamples. The substituents are the same as in the above Formulas exceptwhere defined otherwise or otherwise apparent to the ordinary skilledartisan.

The novel compounds of the present invention can be readily synthesizedusing techniques known to those skilled in the art, such as thosedescribed, for example, in Advanced Organic Chemistry, March, 4^(th)Ed., John Wiley and Sons, New York, N.Y., 1992; Advanced OrganicChemistry, Carey and Sundberg, Vol. A and B, 3^(rd) Ed., Plenum Press,Inc., New York, N.Y., 1990; Protective groups in Organic Synthesis,Green and Wuts, 2^(nd) Ed., John Wiley and Sons, New York, N.Y., 1991;Comprehensive Organic Transformations, Larock, VCH Publishers, Inc., NewYork, N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky andPozharskii, 2^(nd) Ed., Pergamon, New York, N.Y., 2000 and referencescited therein. The starting materials for the present compounds may beprepared using standard synthetic transformations of chemical precursorsthat are readily available from commercial sources, including AldrichChemical Co. (Milwaukee, Wis.); Sigma Chemical Co. (St. Louis, Mo.);Lancaster Synthesis (Windham, N.H.); Ryan Scientific (Columbia, S.C.);Maybridge (Cornwall, UK); Matrix Scientific (Columbia, S.C.); Arcos,(Pittsburgh, Pa.) and Trans World Chemicals (Rockville, Md.).

The procedures described herein for synthesizing the compounds mayinclude one or more steps of protecting group manipulations and ofpurification, such as, recrystallization, distillation, columnchromatography, flash chromatography, thin-layer chromatography (TLC),radial chromatography and high-pressure chromatography (HPLC). Theproducts can be characterized using various techniques well known in thechemical arts, including proton and carbon-13 nuclear magnetic resonance(¹H and ¹³C NMR), infrared and ultraviolet spectroscopy (IR and UV),X-ray crystallography, elemental analysis and HPLC and mass spectrometry(LC-MS). Methods of protecting group manipulation, purification,structure identification and quantification are well known to oneskilled in the art of chemical synthesis.

Appropriate solvents are those which will at least partially dissolveone or all of the reactants and will not adversely interact with eitherthe reactants or the product. Suitable solvents are aromatichydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g,methylene chloride, chloroform, carbontetrachloride, chlorobenzenes),ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether,diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g,acetonitrile, propionitrile), ketones (e.g, 2-butanone, dithyl ketone,tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF),dimethylsulfoxide (DMSO) and water. Mixtures of two or more solvents canalso be used. Suitable bases are, generally, alkali metal hydroxides,alkaline earth metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide;alkali metal hydrides and alkaline earth metal hydrides such as lithiumhydride, sodium hydride, potassium hydride and calcium hydride; alkalimetal amides such as lithium amide, sodium amide and potassium amide;alkali metal carbonates and alkaline earth metal carbonates such aslithium carbonate, sodium carbonate, Cesium carbonate, sodium hydrogencarbonate, and cesium hydrogen carbonate; alkali metal alkoxides andalkaline earth metal alkoxides such as sodium methoxide, sodiumethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metalalkyls such as methyllithium, n-butyllithium, sec-butyllithium,t-bultyllithium, phenyllithium, alkyl magnesium halides, organic basessuch as trimethylamine, triethylamine, triisopropylamine,N,N-diisopropylethylamine, piperidine, N-methyl piperidine, morpholine,N-methyl morpholine, pyridine, collidines, lutidines, and4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO.

As described previously, in preparing the compositions for oral dosageform, any of the usual pharmaceutical media can be employed. Forexample, in the case of oral liquid preparations such as suspensions,elixirs and solutions, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like may be used; or in the caseof oral solid preparations such as powders, capsules and tablets,carriers such as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike may be included. Because of their ease of administration, tabletsand capsules represent the most advantageous oral dosage unit form inwhich solid pharmaceutical carriers are employed. If desired, tabletsmay be coated by standard aqueous or nonaqueous techniques. In additionto the common dosage forms set out above, controlled release meansand/or delivery devices may also be used in administering the instantcompounds and compositions.

It is understood that the functional groups present in compoundsdescribed in the Schemes below can be further manipulated, whenappropriate, using the standard functional group transformationtechniques available to those skilled in the art, to provide desiredcompounds described in this invention.

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

In one protocol, 3-bromobenzoic acid 1 is coupled with t-butyl carbazateby activation with HOBt (hydroxybenzotriazole) in the presence of asuitable carbodiimide such as EDC[1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) anddiisopropylethylamine (DIEA) in dichloromethane or THF to give theprotected hydrazide 2. There are numerous other suitable methods toactivate carboxylic acids for coupling formation (see March J. “AdvancedOrganic Chemistry”, 5th ed., John Wiley & Sons, New York, pp. 506-512(2001). Compound 2 can be converted to a variety of unsymmetricalbiphenyl intermediates 3 by means of a variety of coupling reactions.One type is the Suzuki reaction wherein bromo, iodo, or triflatecompound 2 is reacted with an aryl boronic acid in the presence of apalladium catalyst such as palladium acetate with triphenyl phosphineand aqueous sodium carbonate in a solvent such as toluene and aco-solvent such as n-propanol. (see Suzuki, et al. Chem. Rev., 95, 2457,1995). A variety of aryl boronic acids are commercially available or canbe prepared conveniently from the corresponding aryl bromide or iodideby converting it to an organolithium derivative [Baldwin, J. E., et al.Tetrahedron Lett. 39, 707-710 (1998)], or a Grignard reagent followed bytreatment with trialkylborate [Li, J. J. et al, J. Med. Chem, 38:4570-4578 (1995) and Piettre, S. R., et al. J. Med Chem. 40, 4208-4221(1997)]. Aryl boronates can also be used as an alternative to arylboronic acids in these Pd-catalyzed coupling reactions [Giroux, A., etal., Tetrahedron Lett., 38, 3841 (1997)]. The boronates can be easilyprepared from the aryl bromides, iodides and trifluoromethane sulfonatesusing the method described by Murata, M., et al. [J. Org. Chem. 65:164-168 (2000)]. The Boc protecting group of compound 3 is removed bystandard conditions—trifluoroacetic acid in dichloromethane—to give theTFA salt of hydrazide 4 which can be desalted with aqueous NaOHsolution.

In Scheme 2, a method is described for preparing5-biphenyl-3-substituted-1,2,4-triazole derivatives wherein thesubstitution can be esters, acids, amides, etc. (Catarzi, et al. J. Med.Chem., 38, 2196-2201, 1995). Reaction of hydrazide 4 withcarbethoxy-5-methyl-thioformimidium tetrafluoroborate and triethylaminein dichloromethane gives oxamidrazonate 7 which is cyclized to triazoleester 8. The reagent carbethoxy-5-methyl-thioformimidiumtetrafluoroborate is prepared by reaction of ethyl-2-thiooxamate withtrimethyl oxonium tetrafluoroborate (see Catarzi, et al. above) indichloromethane. Ester 8 can be converted to an amide by heating it withthe corresponding amine, in this case ammonia, in a solvent such asmethanol. Ester 8 can be hydrolyzed to the corresponding acid understandard conditions, and the resulting acid can be converted to an amideunder a variety of conditions such as those described in Scheme 1.Additionally, ester 8 can be reduced to a primary alcohol with, forexample, sodium borohydride (NaBH₄), to provide compounds of Formula (I)wherein R¹ is hydroxymethyl. Alternatively, ester 8 can be converted toa secondary alcohol by reaction with a mixture of lithium borohydrideand a Grignard reagent in an aprotic solvent such as THF. Such primaryor secondary alcohol derived from ester 8 can be further derivatized bya number of methods, including oxidation to a ketone by an oxidizingreagent such as a chromium-based reagent. Such alcohol can also beconverted to a fluoride derivative by, for example, reaction withdiethylaminosulfurtrifluoride (DAST) in dichlormethane at reducedtemperatures.

In Scheme 3, a method is described for preparing an unsubstituted3-triazole ring system (Lin, et al, J. Org. Chem., 44(23), 4160-4165,1979). Ethyl-3-bromobenzoate 10 is reacted with an aryl boronic acid asdescribed in Scheme 1 to give biphenylester 11. The ester 11 provides apreformed biphenyl intermediate that can be further elaborated tocompound 4 and related derivatives as described in earlier Schemes 1-2.In this Scheme 3, ester 11 is converted to amide 12 under standardconditions. Specifically, ester 11 is hydrolyzed to the correspondingacid which is then activated with carbonyldiimidazole (CDI) in DMF,followed by the addition of ammonia in the form of ammonium acetate togive amide 12. Amide 12 in dimethylformamide dimethylacetal is heated togive intermediate 13 which, when heated with hydrazine in acetic acid,gives triazole 14.

In a protocol to prepare 1-biphenyl-3-substituted-1,2,4-triazolederivatives, bromoaniline 22, wherein the amino group is protected witha Boc group, and an arylboronic acid is converted to a variety ofunsymmetrical biphenyl intermediates 23 as described in Scheme 1. TheBoc protecting group of compound 23 is removed as described previouslyand converted to its diazonium salt 24 by standard reaction with sodiumnitrite and HCl in water. Addition of compound 24 to a mixture ofmethylisocyanoacetate and sodium acetate in methanol and water gave thetriazole ester 25. The key intermediate 25 can be then converted to avariety of useful derivatives using the methods described in Schemes1-3.

In a variation to the protocols described in Schemes 1, 3 and 4 above,the Boc-protected anline 26 containing a boronic acid group or boronateester and an aryl bromide, iodide or triflate is converted to a varietyof unsymmetrical biphenyl intermediates 23 as described in Scheme 1.

In accordance with Scheme 6, 31 and 32 can be converted to a biphenylintermediate 33 by using, for example, a Suzuki-Miyaura couplingreaction with a palladium acetate/triphenyl phosphine catalyst system.The biphenyl intermediate 33 can be converted to imidate HCl salt 34under standard Pinner conditions using, for example, a concentratedhydrochloric acid ethanolic solution. The imidate 34 can be converted totriazole 37 by free basing using a biphasic mixture such as EtOAc andNaOH to give ethyl imidate 35, followed by treatment with oxamichydrazide 36, an alcoholic solvent such as ethanol and any one of manyappropriate bases, including a metal acetate base such as potassiumacetate, a tertiary amine base or a metal carbonate base, followed byheating.

In a variation to Scheme 6, the imidate 34 is converted to triazole 37by direct addition of oxamic hydrazide 36, an alcoholic solvent such asethanol and any one of many appropriate bases, including a metal acetatebase such as potassium acetate, a tertiary amine base, or a metalcarbonate base, followed by heating.

In accordance with Scheme 8, compounds of Formulas (I) or (II) whereinR² is H, 38, can be converted by deprotonation with a metal alkoxidebase such as potassium tert-butoxide or sodium tert-butoxide in anappropriate solvent/co-solvent mixture to yield a salt 39.

EXAMPLE 1

3-[3-(2-Trifluoromethoxyphenyl)-phenyl]-1,2,4-triazole Step A:2-Trifluoromethoxyphenylboronic acid

To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxybenzene in 28 Ml of tetrahydrofuran (THF) at −78° C., was carefullyadded a solution of 5.9 Ml of a 1.7 M solution of t-butyl lithium inhexanes (9.5 mmol). This reaction mixture was stirred at −78° C. for 45min. To this reaction mixture at −78° C. was added 2.58 Ml (11.1 mmol)of tri-isopropyl borate and the mixture was slowly warmed to roomtemperature (RT) over a period of 16 h. The reaction mixture was dilutedwith water and made basic with 2N NaOH solution. The reaction mixturewas washed with EtOAc. The aqueous fraction was acidified with 2N HClsolution and stirred for 1 h at RT. The reaction mixture was extractedwith EtOAc and the organic fractions were washed with water, saturatedNaCl solution (brine), dried over Na₂SO₄ and filtered. The filtrate wasconcentrated to give the title compound as a white solid. ¹HNMR (CDCl₃)(δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.53 (ddd, J=9.1, 7.3, 1.8 Hz,1H), 7.38 (td, J=7.3, 0.7 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 5.25 (br s,2H). MS (M+H): 206.9.

Step B: Ethyl-3-(2-Trifluoromethoxyphenyl)-benzoate

To a solution of 0.94 g (4.58 mmol) of ethyl-3-bromobenzoate in 14.5 Mlof toluene at RT was added 0.25 g (0.218 mmol) oftetrakis(triphenylphosphine) palladium(0), 0.94 g (4.58 mmol) of2-trifluoromethoxyphenylboronic acid, 2.22 Ml (4.45 mmol) of 2M aqueoussodium carbonate solution and 7 Ml of ethanol. The reaction mixture washeated at reflux for 18 h. The reaction mixture was cooled and dilutedwith ethyl acetate and water. The organic fraction was separated andwashed with saturated NaCl solution (brine), dried over MgSO₄, filteredand the filtrate was concentrated to an oil which was purified bychromatography (silica, 1%, 5%, 30% successively ethyl acetate:hexanes)to give the title compound. ¹H NMR (CD₃OD) (δ, ppm): 8.02 (s, 1H), 7.97(dd, J=7.8, 1.2 Hz, 1H), 7.60 (dd, J=7.7, 1.3 Hz, 1H), 7.50-7.33 (m,5H), 4.31 (q, 2H), 1.31 (t, 3H). Mass Spectrum (ESI) m/e (M+1): 311.2.

Step C: 3-(2-Trifluoromethoxyphenyl)-benzoic acid

A solution of 0.3 g (4.19 mmol) ofethyl-3-(2-trifluoromethoxyphenyl)-benzoate and 8.3 Ml (8.3 mmol) of a1N solution of NaOH in 12.5 Ml of methanol was stirred 18 h at RT. Thereaction mixture was concentrated and the Ph was adjusted to Ph=2 with 1N HCl solution. The mixture was extracted with ethyl acetate (EtOAc) andthe organic fraction was dried over MgSO₄, filtered and the filtrate wasconcentrated to give the title compound as a white solid that was usedwithout further purification.

Step D: 3-(2-Trifluoromethoxyphenyl)-benzamide

To a solution of 0.94 g (3.36 mmol) of3-(2-trifluoromethoxyphenyl)-benzoic acid in 17 Ml of DMF was added 0.55g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction was stirredat RT for 4 h. To the reaction mixture was added 2.6 g (33.6 mmol) ofammonium acetate and the reaction mixture was stirred over night at RT.The reaction mixture was partitioned between ethyl acetate and water andthe organic fraction was washed with brine, dried over MgSO₄, filteredand the filtrate was concentrated. The residue was purified bychromatography (silica, 30%, 50% successively EtOAc:hexanes) to give thetitle compound. Mass Spectrum (ESI) m/e (M+1): 282.2.

Step E: 3-[3-(2-Trifluoromethoxyphenyl)-phenyl]-1,2,4-triazole

A solution of 0.137 g (0.48 mmol) of3-(2-trifluoromethoxyphenyl)-benzamide in 1 Ml of N,N-dimethylformamidedimethyl acetal was heated at 120° C. for 2 h at which time the reactionwas concentrated in vacuo. To this material in 2.3 Ml of acetic acid wasadded 0.028 g (0.55 mmol) of hydrazine hydrate and the reaction mixturewas heated at 90° c. for 2 h. The reaction mixture was then concentratedand partitioned between EtOAc and saturated NaHCO₃ solution. The organicfraction was washed with brine, dried over MgSO₄, filtered and thefiltrate was concentrated. The residue was purified by chromatography(silica, 30:1, 9:1, 3:1 successively CH₂Cl₂:acetone) to give the titlecompound. ¹H NMR (CD₃OD) (δ, ppm): 8.32 (s, 1H), 8.06 (s, 1H), 7.98 (m,1H), 7.50 (m, 3H), 7.39 (m, 3H). Mass Spectrum (ESI) m/e (M+1): 306.1.

The following Examples 2-7 were prepared using procedures similar tothat described in Example 1. The preparation of any intermediates thatwere not commercially available are described.

EXAMPLE 2

3-[3-(2-Trifluoromethyphenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 290.1.

EXAMPLE 3

3-[3-(2-(2,2,2-Trifluoroethoxyphenyl)-phenyl]-1,24-triazole Step A:2-(2,2,2-Trifluoroethoxy)phenyl bromide

A solution of 0.35 g (2 mmol) of 2-bromophenol, 0.63 g (3 mmol) of2,2,2-trifluoroethyliodide, 0.55 g (4 mmol) of potassium carbonate in 2Ml of DMF was reacted at 150° C. in a microwave system (PersonalChemistry, Smithcreator) for 30 min. After cooling to RT, the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic fraction was dried over MgSO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (5%, 10%successively EtOAc:hexanes) to give the title compound.

Step B: Ethyl-3-(2-(2,2,2-trifluoroethoxyphenyl)-benzoate

To a solution of 2.5 g (9.8 mmol) of 2-trifluoroethoxyphenyl bromide in33 Ml of toluene at RT was added 0.57 g (0.49 mmol) oftetrakis(triphenyl-phosphine) palladium(0), 0.2 g (10.3 mmol) of3-ethoxycarbonylphenylboronic acid, 5.9 Ml (11.8 mmol) of 2M aqueoussodium carbonate solution and 17 Ml of ethanol. The reaction mixture washeated at reflux for 18 h. The reaction mixture was cooled and dilutedwith ethyl acetate and water. The organic fraction was separated andwashed with saturated NaCl solution (brine), dried over MgSO₄, filteredand the filtrate was concentrated to an oil which was purified bychromatography (silica, 1%, 5%, 30% successively ethyl acetate:hexanes)to give the title compound. Mass Spectrum (ESI) m/e (M+1): 325.1.

Step C: 3-[3-(2-(2,2,2-Trifluoroethoxyphenyl-phenyl]-1,2,4-triazole

The title compound can be prepared using procedures similar to thatdescribed in Example 1, Steps C-E.

EXAMPLE 4

3-[3-((2,4-Bis-trifluoromethyl)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 358.3.

EXAMPLE 5

3-[3-((2-Trifluoromethyl-5-fluoro)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 308.0.

EXAMPLE 6

3-[3-((2-Trifluoromethoxy)phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 324.1.

EXAMPLE 7

3-[3-((2-Trifluoromethoxy)-phenyl)-(6-fluoro)phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 324.0.

EXAMPLE 8

3-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-(4-fluoro)phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 338.0.

Step A: Methyl-3-((2-hydroxy)phenyl)-4-fluorobenzoate

To a solution of 2 g (8.45 mmol) of methyl-3-bromo-4-fluorobenzoate in28 Ml of toluene at RT was added 0.49 g (0.42 mmol) oftetrakis(triphenyl phosphine)palladium(0), 1.95 g (8.9 mmol) of2-(4,4,5,5,-tetramethyl-1.3.2-dioxaborolan-2-yl)phenol, 5.1 Ml (10.15mmol) of 2M aqueous sodium carbonate solution and 14 Ml of n-propanol.The reaction mixture was heated at reflux for 18 h. The reaction mixturewas cooled and diluted with ethyl acetate and water. The organicfraction was separated and washed with saturated NaCl solution (brine),dried over MgSO₄, filtered and the filtrate was concentrated to an oilwhich was purified by chromatography (silica, 90:1, 30:1 successivelyCH₂Cl₂:acetone) to give the title compound. Mass Spectrum (ESI) m/e(M+1): 247.0.

Step B: Methyl-3-((2-(2,2,2-trifluoroethoxy)phenyl)-4-fluorobenzoate

A mixture of 1.7 g (7.1 mmol) ofmethyl-3-((2-hydroxy)phenyl)-4-fluorobenzoate, 2.46 g (10.6 mmol) of2,2,2,-trifluoroethyl trifluoromethanesulfonate and 3.45 g (10.6 mmol)of cesium carbonate in 35 Ml of DMF was stirred at 60° C. for 18 h. Thecooled reaction mixture was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc and the combined organicfractions were washed with water, brine, dried over MgSO₄ and filtered.The filtrate was concentrated and purified by chromatography (silica,5%, 30% successively EtOAc:hexanes) to give the title compound as awhite solid. Mass Spectrum (ESI) m/e (M+1): 329.0.

Step C:3-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-(4-fluoro)phenyl]-1,2,4-triazole

The title compound can be prepared using procedures similar to thatdescribed in Example 1, Steps C-E.

EXAMPLE 9

5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole StepA: 3-Bromophenylcarbonyl-(N-t-butoxycarbonyl)hydrazide

A solution of 1 g (4.97 mmol) of 3-bromobenzoic acid, 0.59 g (4.52 mmol)of t-butylcarbazate, 0.95 g (4.97 mmol) of EDC[1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), 0.67 g (4.97 mmol) ofhydroxybenzotriazole (HOBt) and 3.15 Ml (18.1 mmol) ofdiisopropylethylamine in 23 Ml of CH₂Cl₂ was stirred at RT for 18 h. Thereaction mixture was diluted with CH₂Cl₂ and washed with 1N HClsolution, saturated NaHCO₃ solution and brine. The solution was driedover MgSO₄, filtered and the filtrate was concentrated. The residue waspurified by chromatography (silica, 30:1, 9:1, 3:1 successivelyCH₂Cl₂:acetone) to give the title compound.

Mass Spectrum (ESI) m/e (M): 314.0, (M+2): 316.0

Step B: 3-((2-Trifluoromethoxy)phenyl)-phenylhydrazide

A solution of 0.22 g (1.07 mmol) of 2-trifluoromethoxyphenylboronic acidand 0.32 g (1.02 mmol) of3-bromophenylcarbonyl-N-t-butoxycarbonylhydrazide in 5 Ml of toluene and2.5 Ml of n-propanol was stirred for 30 min. To this reaction mixturewas added 0.0007 g (0.003 mmol) of palladium acetate, 0.0024 g (0.009mmol) of triphenylphosphine and 0.61 Ml (1.2 mmol) of a 2M aqueoussodium carbonate solution and the reaction mixture was heated at refluxfor 18 h. The reaction mixture was cooled and diluted with EtOAc andwater. The organic fraction was dried over MgSO₄, filtered and thefiltrate was concentrated. The residue was purified by chromatography(silica, 30:1, 9:1 successively, CH₂Cl₂:acetone) to give the protectedhydrazide which was then dissolved in a mixture of 2.1 Ml of TFA and 2.1Ml of CH₂Cl₂. The reaction mixture was stirred for 2 h whereupon it wasconcentrated, dissolved in CH₂Cl₂ and washed with 1N NaOH solution. Theorganic fraction was dried over MgSO₄, filtered and the filtrate wasconcentrated to give the tile compound as a white solid. Mass Spectrum(ESI) m/e (M+1): 297.1.

Step C:5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole

To a solution of 0.093 g (0.98 mmol) of acetamidine hydrochloride in 1.1Ml of ethanol was added 0.22 Ml (0.98 mmol) of a 25% solution of sodiummethoxide in methanol and the reaction mixture was stirred for 30 min.whereupon it was filtered. To the filtrate was added 0.19 g (0.66 mmol)of 3-((2-trifluoromethoxy)phenyl)-bromophenylhydrazide and the reactionmixture was stirred over night. The reaction mixture was concentratedand purified by chromatography (silica, 3%, 10%, 30% successively,methanol:CH₂Cl₂) to give a white solid. The white solid was heated(neat) to its melting temperature for 30 min. The reaction was cooled toRT, dissolved in CH₂Cl₂ and concentrated. The residue was purified bychromatography (silica, 3%, 10%, successively, methanol:CH₂Cl₂) to givethe title compound as a white solid. ¹H NMR (CD₃OD) (δ, ppm): 8.00 (s,1H), 7.93 (m, 1H), 7.49-7.34 (m, 6H), 2.41 (s, 3H). Mass Spectrum (ESI)m/e (M+1): 320.5.

The following Examples 10 to 18 were prepared according to the proceduredescribed in Example 9, using the corresponding substituted amidine.

EXAMPLE 10

5-Methyl-3-[3-((2-trifluoromethyl)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 304.0.

EXAMPLE 11

5-Methyl-3-[3-((2,4-bis(trifluoromethyl)-phenyl)-)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 372.5.

EXAMPLE 12

5-Methyl-3-[3-((2-(2,2,2-trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 334.1.

The title compound was prepared from the acid ofethyl-3-(2-trifluoroethoxyphenyl)-benzoate which was prepared in Example3, Step B.

EXAMPLE 13

5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 338.1.

EXAMPLE 14

5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-(6-fluoro)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 338.1.

EXAMPLE 15

5-Methyl-3-[3-((2-(2,2,2-trifluoroethoxy)phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 352.0.

The title compound was prepared from the acid ofMethyl-3-(2-trifluoroethoxy-(4-fluoro)-phenyl)-benzoate which wasprepared in Example 8, Step B.

EXAMPLE 16

5-Cyclopropyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 346.2.

EXAMPLE 17

5-Trifluoromethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 374.1.

EXAMPLE 18

5-Methyl-3-[3-((2-trifluormethxy-5-fluoro)-phenyl)-phenyl]-1,2,4-triazole

Mass Spectrum (ESI) m/e (M+1): 321.9.

EXAMPLE 19

3-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamideStep A: Ethyl-N¹-3-(2-trifluoromethoxy)-benzoyl-N²-oxamidrazonate

To a solution of 0.45 g (1.54 mmol) of3-(2-trifluoromethoxyphenyl)-bromophenylhydrazide (Example 9, Step B) in20 Ml of CH₂Cl₂ was added 0.54 g (2.3 mmol) ofcarbethoxy-5-methylthioformimidium tetrafluoroborate and 0.43 Ml (3.08mmol) of triethylamine and the reaction was stirred at refluxingtemperatures for 4 hr. The reaction mixture was cooled to RT, washedwith water, dried over Na₂SO₄, filtered and the filtrate wasconcentrated to a solid. Two Ml of CH₂Cl₂ was added and the resultingsolid product was recovered by filtration. Mass Spectrum (ESI) m/e(M+1): 396.1.

Step B:5-Ethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxylate

The solid Ethyl-N¹-3-(2-trifluoromethoxy)-benzoyl-N²-oxamidrazonate(0.25 g, 0.616 mmol) was heated in an oil bath above its melting pointfor 20 min. After cooling to RT, the residue was dissolved in CH₂Cl₂ andconcentrated to give a yellow solid. It was purified by chromatography(silica, 10%, 30%, 50% successively, EtOAc:hexanes) to give a whitesolid. Mass Spectrum (ESI) m/e (M+1): 378.1.

Step C:3-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

A solution of 0.13 g (0.34 mmol) of5-ethyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-5-carboxylatein 2 Ml of methanol in a tube was saturated with ammonia. The tube wassealed and the reaction mixture was heated at 60° C. overnight. Thereaction mixture was then concentrated and the residue was purified bychromatography (silica, 3%, 10%, 20% successively methanol:CH₂Cl₂) togive the title compound. ¹H NMR (CD₃OD) (δ, ppm): 8.10 (s, 1H), 8.02 (m,1H), 7.54-7.36 (m, 6H). Mass Spectrum (ESI) m/e (M+1): 349.2.

EXAMPLE 20

3-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-4-fluorophenyl]-1,2,4-triazole-5-carboxamideStep A: 3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-4-fluorobenzoic acid

To a solution of 0.75 g (2.29 mol) of Methyl1-3-((2-trifluoroethoxy)phenyl)-4-fluorobenzoate (Example 8, Step B) in11.5 Ml of a 3:1 mixture of THF:water was added 0.164 g (6.86 mmol) ofLiOH and the reaction mixture was stirred at RT for 18 hr. The reactionmixture was concentrated and the Ph was adjusted to Ph=2 with 1N HClsolution. The mixture was extracted with EtOAc and the combine organicfractions were washed with brine, dried over MgSO₄, filtered and thefiltrate was concentrated to give the title compound which was usedwithout further purification.

Step B:3-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-4-fluorophenyl]-1,2,4-triazole-5-carboxamide

The title compound was prepared from3-((2-trifluoroethoxy)phenyl)-4-fluorobenzoic acid according toprocedures described in Example 9 Steps A&B and Example 19. ¹H NMR(CD₃OD) (δ, ppm): 8.02 (m, 2H), 7.99 (m, 1H), 7.39 (m, 1H), 7.30 (m,1H), 7.16 (m, 2H), 4.45 (q, J=8.5 Hz, 2H). Mass Spectrum (ESI) m/e(M+1): 381.0.

The following Examples 21-26 were prepared according to proceduresdescribed in Examples 19 and 20.

EXAMPLE 21

3-[3-((2-Trifluoromethyl)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 333.1.

EXAMPLE 22

3-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 363.1.

EXAMPLE 23

3-[3-((2-Trifluoromethoxy)-phenyl)-(6-fluoro)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 367.0.

EXAMPLE 24

3-[3-((2-Trifluoromethyl-5-fluoro)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 351.0.

EXAMPLE 25

3-[3-((2-Trifluoromethoxy)-phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 367.0.

Step A: Preparation of 4-fluoro-3-(2-trifluoromethoxyphenyl)benzonitrile

3-bromo-4-fluorobenzonitrile (1.0 equivalent),2-(trifluoromethoxy)benzeneboronic acid (1.25 equivalent), palladiumacetate (0.005 equivalent) and triphenylphosphine (0.01 equivalent) weresequentially charged to a multi-necked flask. After purging the flaskwith nitrogen, toluene (5 mL/gram of 3-bromo-4-fluorobenzonitrile) wasadded and the resulting slurry was stirred while bubbling nitrogensubsurface for about 20 minutes. In a separate flask, an aqueouspotassium phosphate solution was prepared by dissolving solid potassiumphosphate (2.0 equivalents) into water (2 mL/gram of potassiumphosphate). The resulting solution was de-oxygenated by bubblingnitrogen subsurface while stirring for about 30 minutes. The aqueouspotassium phosphate solution was added to the toluene slurry and thereaction mixture was warmed to 60-65° C. by heating with steam. Theprogress of the reaction was monitored by HPLC and the reactiontemperature was held between 63-69° C. When 3-bromo-4-fluorobenzonitrilewas consumed, heating was discontinued and the reaction mixture wascooled to RT using an ice bath. The aqueous layer was siphoned from thevessel and Ecosorb C-941 (0.5 gram/grams of3-bromo-4-fluorobenzonitrile, commercially available from GraverTechnologies, Glasgow, Del.) was added to the reaction vessel. Theresulting black slurry was stirred at RT for 15 hours. The carbon wasremoved by filtering the slurry through a pad of solka flok on a filterpot. The filter cake was washed with toluene (4 mL/gram of3-bromo-4-fluorobenzonitrile). The combined filtrates were batchconcentrated (40-50° C.) to provide the biaryl nitrile product as athick, light-orange oil (94.0% yield).

Step B: Preparation of

Absolute ethanol (1.8 mL/gram of biaryl nitrile) was charged to a roundbottom flask. The stirred ethanol was chilled with an ice/acetone bathand gaseous hydrogen chloride was bubbled subsurface while the internaltemperature was maintained less than 20° C. Addition of HCl wasmonitored by proton titration using a Metrohm 808 Titrando (commerciallyavailable from Metrohm Ltd.) to determine HCl concentration of theethanol solution. The addition was stopped after the concentration ofHCl reached 38% (7.5 equivalents). The biaryl nitrile from step A (1.0equivalent) was added as a neat oil to the chilled ethanolic HClsolution and the reaction solution was allowed to warm to RT while beingstirred overnight (>15 h). The reaction was deemed complete when assayby HPLC showed no presence of the starting biaryl nitrile. The resultingreaction was then diluted with toluene (8 mL/gram of biaryl nitrile). Toinduce crystallization, the batch was solvent switched to toluene byco-distillation with ethanol (<35° C. internal temperature) whichazeotropically removed ethanol. This process was carried out until theethanol content in the mother liquor was less than 1 mol % relative totoluene. This endpoint was determined by proton NMR in CDCl₃ of themother liquor. The solids were isolated by filtration, washed withtoluene (2.3 mL/gram of biaryl nitrile). The white crystalline HCl saltof the ethyl imidate product was dried under a stream of nitrogen.

Step C: Preparation of

The imidate HCl salt from Step B (1.0 equivalent) and EtOAc (4 mL/gramof imidate HCl salt) were added to a flask, followed by stirring to givea heterogeneous slurry. This slurry was cooled to 10° C. followed by theslow addition of a solution of 5.0 N NaOH (3.3 equivalents). The rate ofaddition of the NaOH solution was periodically adjusted to maintain thereaction temperature below 15° C. Once the addition of NaOH wascomplete, the biphasic reaction mixture was allowed to warm to ambienttemperature at which point all of the solids had dissolved (ca. 30 min).Stirring was stopped and the two layers were allowed to separate. Thebottom aqueous layer was removed and discarded. To the flask containingthe organic layer was added water (2 mL/gram of HCl imidate salt) andthe resulting biphasic mixture was stirred for 5 minutes. The layerswere allowed to separate and the bottom aqueous layer was removed anddiscarded. This was followed by the addition of a 10% NaCl aqueoussolution (2 mL/gram of HCl imidate salt) to the flask. The resulting twolayers were stirred for 5 minutes, and the bottom aqueous layer wasremoved and discarded. The top organic layer was transferred to a roundbottom flask that was connected to a batch concentrator. A solventswitch from EtOAc to EtOH was then performed by removing the EtOAc byco-distillation with EtOH. Once the solvent switch was complete (<3%EtOAc by ¹H NMR, imidate concentration approximately 185 mg/mL), theethanolic solution containing the free base imidate was transferred to anew flask.

Oxamic hydrazide (1.1 equivalents) and potassium acetate (5.0equivalents) were added to the ethanol solution containing the imidatefrom above. The resulting heterogeneous mixture was then heated tobetween 60-70° C. using a steam batch along with vigorous stirring. Thereaction was monitored by HPLC analysis for conversion of the imidate tothe desired triazole product. Once the reaction was complete, it wascooled to ambient temperature followed by the slow addition of water (4mL/gram of imidate HCl salt) to crystallize the desired product from thereaction. The desired product was then collected by vacuum filtration asan off-white solid (85% yield).

Step D: Preparation of

The triazole product of Step C (1.0 equivalents) was added to a reactionvessel, followed by the addition of toluene (5.3 mL/gram of triazole)and THF (1.7 mL/gram of triazole). The resulting heterogeneous mixturewas stirred at ambient temperature. To this slurry was added a solutionof potassium tert-butoxide (1.1 equivalents). The rate of addition ofthe base was periodically adjusted to maintain the reaction temperaturebelow 35° C. As the addition proceeded, the reaction mixture became lessheterogeneous. Once the addition of the base was complete, the nowhomogeneous light yellow solution was allowed to stir at ambienttemperature for 30 min. At this point, water (2.5 equivalents) wasslowly added (ca. 10 min) to the batch with no noticeable exotherm.After about 15 min, the reaction became increasingly cloudy and thebatch temperature slowly began to rise. Approximately 20 min afteraddition of water, solids began to form indicating the crystallizationhad begun. After about 30 min, the batch temperature had reached itsmaximum (24.9° C.). The heterogeneous batch was allowed to stir for anadditional 30 minutes. The batch was filtered onto a filter pot usingthe mother liquor to obtain any residual solids in the reaction vessel.The wet cake was washed with fresh toluene (4 mL/gram of triazole). Thebatch was transferred to a vacuum oven and dried at 45° C. and 100 torrfor 24 hours to provide the potassium salt dihydrate product as a whitesolid (95% yield).

EXAMPLE 26

3-[3-((2,4-bis(trifluoromethyl)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 401.0.

EXAMPLE 26 AND 26′

2-Methyl-3-[3-((2-trifluoromethoxy)-phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole-5-carboxamide(26) and1-Methyl-3-[3-((2-trifluoromethoxy)-phenyl)-(4-fluoro)-phenyl]-1,24-triazole-5-carboxamide(26′)

To a solution of 0.12 g (0.328 mmol) of3-[3-((2-trifluoromethoxy)phenyl)-(4-fluoro)-phenyl]-1,2,4-triazole-5-carboxamide(Example 25) in 1.5 Ml of methanol was added 0.1 Ml (0.46 mmol) of asolution of NaOCH₃ (25% in methanol) and 0.02 Ml of methyl iodide. Thetube was sealed and heated overnight at 100° C. The reaction mixture wasconcentrated and the residue was purified by chromatography (silica,30:1, 9:1, 1% successively methanol:CH₂Cl₂) to give the title compounds.

(26) ¹H NMR (CD₃OD) (δ, ppm); 8.09 (m, 1H), 8.00 (dd, J=7.1, 2.3 Hz,1H), 7.50-7.36 (m, 4H), 7.23 (t, J=9.2 Hz, 1H), 4.18 (s, 3H). MassSpectrum (ESI) m/e (M+1): 381.0

(26′ ¹H NMR (CD₃OD) (δ, ppm): 7.84 (m, 1H), 7.77 dd, J=6.6, 2.3 Hz, 1H),7.52-7.44 (m, 5H), 4.00 (s, 3H). Mass Spectrum (ESI) m/e (M+1): 381.0.

The following Examples 27/27′ and 28/28′ were prepared according to theprocedure described in Example 26 and 26′.

EXAMPLE 27 AND 27′

2-Methyl-3-[3-((2-(2,2,2-trifluoroethoxy)phenyl)-4-fluorophenyl]-1,2,4-triazole-5-carboxamide(27) and1-Methyl-3-[3-((2-(2,2,2-trifluoroethoxy)phenyl)-4-fluorophenyl]-1,2,4-triazole-5-carboxamide(27′)

(27) Mass Spectrum (ESI) m/e (M+1): 395.2.

(27′) Mass Spectrum (ESI) m/e (M+1): 395.2.

EXAMPLE 28 AND 28′

2,5-dimethyl-3-[3-((2-trifluoromethoxy)-phenyl)-4-fluorophenyl]-1,2,4-triazole(28) and1,5-dimethyl-3-[3-((2-trifluoromethoxy)-phenyl)-4-fluorophenyl]-1,2,4-triazole-5-carboxamide(28′)

(28) Mass Spectrum (ESI) m/e (M+1): 334.2.

(28′) Mass Spectrum (ESI) m/e (M+1): 334.2.

EXAMPLE 29

N-Methyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

To a solution of 0.083 g (0.24 mmol) of3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxylicacid (made from5-ethyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-5-carboxylateExample 19 according to procedures described in Example 20) in 1.2 Ml ofDMF at RT was added 0.038 g (0.24 mmol) of carbonyldiimidazole (CDI) andthe reaction mixture was stirred for 3 hr. To the reaction mixture wasadded 1.2 Ml (2.4 mmol) of a 2M solution of methylamine in THF and thereaction mixture was stirred overnight at RT. The reaction mixture wasconcentrated and partitioned between EtOAc and water. The aqueousfraction was extracted with EtOAc and the combined organic fractionswere washed with water and brine, dried over MgSO₄, filtered and thefiltrate was concentrated. The residue was purified by chromatography(silica, 30%, 50% successively EtOAc:hexanes) to give the title compoundas a foamy white solid. Mass Spectrum (ESI) m/e Mass Spectrum (ESI) m/e(M+1): 363.0.

The following Examples 30 and 31 were prepared using the proceduredescribed in Example 29.

EXAMPLE 30

N-Ethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 377.2.

EXAMPLE 31

N,N-Diethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

Mass Spectrum (ESI) m/e (M+1): 405.0.

EXAMPLE 32

5-(1-Hydroxy-ethyl)-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

To a solution of 0.007 Ml (0.133 mmol) of a 2M solution of LiBH₄ in THFat RT was added a solution 0.18 Ml (0.53 mmol) of a 3M solution ofMeMgCl in THF. After stirring, the reaction mixture was cooled to −20°C. and to it was added a solution of 0.1 g (0.265 mol) of5-ethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxylate(Example 19) in 1 Ml of THF and the reaction mixture was stirred at −20°C. for 24 hr. The reaction mixture was poured into cold 1N HCl solution.The aqueous fraction was extracted with diethyl ether and the combinedorganic fractions were washed with brine, dried over MgSO₄, filtered andthe filtrate was concentrated. The residue was purified bychromatography (silica, 9:1, CH₂Cl₂, acetone) to give the titlecompound. Mass Spectrum (ESI) m/e (M+1): 350.1.

EXAMPLE 33

5-(1-Hydroxy-1-methyl-ethyl)-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound is a by-product of Example 32.

Mass Spectrum (ESI) m/e (M+1): 364.1.

EXAMPLE 34

5-Hydroxymethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound is a by-product of Example 32.

Mass Spectrum (ESI) m/e (M+1): 336.1.

EXAMPLE 35

5-(1-Fluoro-ethyl)-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

To a solution of 0.13 g (0.37 mmol) of5-(2-hydroxy)-ethyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazolein 2 Ml of CH₂Cl₂ at −78° C. was added 0.06 Ml of(diethylamino)sulfurtrifluoride (DAST) and the reaction was stirred at−78° C. for 1 hr. The reaction was quenched with a saturated solution ofNaHCO₃. The organic fraction was washed with brine, dried over MgSO₄,filtered and the filtrate was concentrated. The residue was purified bychromatography (silica, 9:1 CH₂Cl₂:acetone) to give the title compound.Mass Spectrum (ESI) m/e (M+1): 352.0.

EXAMPLE 36

5-(Acetyl)-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

To a suspension of 0.155 g (1.59 mmol) of N,O-dimethylhydroxylaminehydrochloride in 1.6 Ml of benzene at 5° C. was added 0.8 Ml (1.59 mmol)of a 2M solution of trimethylaluminum in toluene. The reaction mixturewas warmed to RT and stirred for 1 hr. This solution was then addeddropwise to a solution of 0.3 g (0.79 mmol) of5-ethyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-5-carboxylatein 8 Ml of benzene and the reaction mixture was heated at reflux for 18hr. The reaction mixture was cooled to RT and quenched with a 5%solution of HCl. The aqueous fraction was extracted with EtOAc and thecombined organic fractions were dried over MgSO₄, filtered and thefiltrate was concentrated. The residue was purified by chromatography(silica 10% methanol:CH₂Cl₂) to give the intermediate amide.

To a solution of 0.19 g (0.49 mmol) of the amide in 2.5 Ml of THF at 0°C. was added 0.41 Ml (1.22 mmol) of a 3M solution of methylmagnesiumchloride in THF and the reaction was stirred at 0° C. for 1 hr, warmedto RT and stirred for 18 hr. The reaction mixture was partitionedbetween EtOAc and saturated NH₄Cl solution. The organic fraction waswashed with saturated NaHCO₃ solution, and brine. It was then dried overMgSO₄, filtered and the filtrate was concentrated. The residue solid wastriturated with CH₂Cl₂ and the title compound was isolated as a solid byfiltration. Mass Spectrum (ESI) m/e (M+1): 348.1.

EXAMPLE 37

1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxamideStep A: 3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-aniline

To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide(Example 3, Step A) in 39 Ml of toluene was added 0.136 g (0.118 mmol)of tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of3-aminophenylboronic acid, 47 Ml (94.1 mmol) of a 2M solution of sodiumcarbonate and 8 Ml of ethanol and the reaction mixture was heated at 90°C. for 22 hr. The reaction mixture was cooled to RT, and partitionedbetween water and EtOAc. The aqueous fraction was extracted with EtOAcand the combined organic fractions were washed with water and brine anddried over Na₂SO₄, filtered and the filtrate was concentrated. Theresidue was purified by chromatography (silica, 4:1 hexanes:EtOAc) togive the title compound. Mass Spectrum (ESI) m/e M+1 268.1.

Step B:Methyl-1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxylate

To a solution of 0.923 g (3.45 mmol) of3-((2-trifluoroethoxy)-phenyl)analine in 6 Ml of a 1N solution of HCl at0° C. was added 0.238 g (3.45 mmol) of sodium nitrite and 1 Ml of waterand the reaction mixture was stirred for 20 min. to give the diazoniumsalt solution.

To a solution of 0.27 g (2.76 mmol) of methylisocyanoacetate in 15 Ml ofmethanol and 2 Ml of water at 0° C. was added 1.8 g (22.08 mmol) ofsodium acetate. To this reaction mixture was added dropwise thediazonium salt solution and the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was then diluted with methanol andconcentrated. The residue was diluted with EtOAc and 0.5N HCl solution.The aqueous layer was extracted with EtOAc and the combined organicfractions were washed with 5% NaHCO₃ solution, brine, dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified bychromatography (silica, 1:1 EtOAc:hexanes) to give the title compound.Mass Spectrum (ESI) m/e M+1 378.1.

Step C:1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxylicacid

A solution of 0.29 g (0.769 mmol) ofmethyl-1-[3-((2-trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxylateand 2.2 Ml (2.2 mmol) of a 1M solution of NaOH in water was stirred for18 hr at RT. The reaction mixture was concentrated. The residue wasdiluted with water and the Ph was adjusted to 2-4 with 1N HCl solution.The mixture was extracted with EtOAc and the combined organic fractionswere washed with brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated to give the title compound. Mass Spectrum (ESI) m/eM+1363.9.

Step D:1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

To a solution of 0.225 g (0.619 mmol) of1-[3-((2-trifluoroethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxylicacid in 3.1 Ml of DMF was added 0.1 g (0.19 mmol) of CDI and thereaction mixture was stirred at RT for 4 hr. To the reaction mixture wasadded 0.477 g (6.19 mmol) of ammonium acetate and the reaction mixturewas stirred for 19 hr. The reaction mixture was diluted with water andEtOAc and the aqueous layer was extracted with EtOAc. The combinedorganic fractions were washed with brine, dried over Na₂SO₄, filteredand the filtrate was concentrated. The residue was purified bychromatography (silica, 1:1 EtOAc:hexanes, 1% methanol:CH₂Cl₂, 10%methanol:CH₂Cl₂) to give the title compound. Mass Spectrum (ESI) m/e M+1363.1.

EXAMPLE 38

1-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxamideStep A: 1-N-t-butoxycarbonylamino-3-bromobenzene

A solution of 10 g (58.13 mmol) of 3-bromoaniline and 15.2 g (69.75mmol) of Boc₂O in 300 Ml of toluene was heated overnight at 70° C. Thereaction mixture was concentrated and diluted with EtOAc and 0.5N HClsolution. The organic fraction was washed with 0.5N HCl solution andbrine. It was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (hexanes, 9:1hexanes:EtOAc successively) to give the title compound.

Step B: 1-N-t-butoxycarbonyl-3-((2-Trifluoromethoxy)-phenyl)analine

1-N-t-Butoxycarbonylamino-3-bromobenzene was coupled with2-trifluoromethoxyphenylboronic acid according to procedures describedin Example 37, Step A.

Step C: 3-((2-Trifluoromethoxy)-phenyl)aniline

A solution of 0.977 g (2.77 mmol) of1-N-t-butoxycarbonyl-3-((2-Trifluoromethoxy)-phenyl)analine in 7 Ml ofTFA and 7 Ml of CH₂Cl₂ was stirred at RT for 1 hr. The reaction mixturewas concentrated and the residue was diluted with 1N NaOH solution andEtOAc. The organic fraction was washed with 1N NaOH solution and brine,dried over Na₂SO₄ filtered and the filtrate was concentrated to give thetitle compound. Mass Spectrum (ESI) m/e M+1 254.1.

Step D:1-[3-((2-Trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

The title compound was prepared from3-((2-Trifluoro-methoxy)phenyl)aniline according to procedures describedin Example 37. Mass Spectrum (ESI) m/e M+1 349.1.

The following Examples 39-40 were prepared according to the proceduresdescribed in Examples 37 or 38.

EXAMPLE 39

1-[3-((2,4-bis-trifluoromethyl)phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 401.1.

EXAMPLE 40

1-[3-((2-(2,2,2-Trifluoroethoxy-4-fluoro)phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 381.2.

The following Examples 41 to 44 were prepared according to proceduresdescribed in Example 29.

EXAMPLE 41

N-Methyl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 363.1.

EXAMPLE 42

N-Ethyl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 377.1.

EXAMPLE 43

N,N-Diethyl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,24-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 405.2.

EXAMPLE 44

N-(2-Hydroxyeth-1-yl)-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,24-triazole-3-carboxamide

Mass Spectrum (ESI) m/e M+1 393.1.

EXAMPLE 45

3-(1-Hydroxy)eth-1-yl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole

The title compound was prepared according to procedures described inExample 32. Mass Spectrum (ESI) m/e M+1 350.1.

EXAMPLE 46

3-(1-Hydroxy-1-methyl)eth-1-yl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole

The title compound was isolated according to the procedure for preparingthe compound of Example 45. Mass Spectrum (ESI) m/e M+1 364.0.

EXAMPLE 47

3-Hydroxymethyl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound was isolated according to the procedure for preparingthe compound of Example 45. Mass Spectrum (ESI) m/e M+1 336.1.

EXAMPLE 48

3-(1-Fluoro)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound was prepared from3-(1-hydroxy)-eth-1-yl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole(Example 45) according to procedures described in Example 35. MassSpectrum (ESI) m/e M+1 352.0.

EXAMPLE 49

3-(1-Fluoro-1-methyl)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound was prepared from3-(1-hydroxy-1-methyl)eth-1-yl-1-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole(Example 46) according to procedures described in Example 35.

Mass Spectrum (ESI) m/e M+1 366.1.

EXAMPLE 50

3-(1-Oxo)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound was prepared from1-[3-((2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxylicacid (from Example 38) according to procedures described in Example 36.Mass Spectrum (ESI) m/e M+1 348.1.

EXAMPLE 51

3-(1-Amino)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

A solution of 0.037 g (0.106 mmol) of3-(1-oxo)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole(Example 50), 0.082 g (1.06 mmol) of NH₄Oac and 0.1 Ml (0.72 mmol) oftriethylamine in 1 Ml of THF was stirred for 2 hr. To the reactionmixture was added 0.045 g (0.212) of sodium triacetoxy-borohydride and0.02 Ml (0.212 mmol) of acetic acid. The reaction mixture was stirred atRT for 72 hr. The reaction mixture was diluted with Saturated NaHCO₃solution and the mixture was stirred for 45 min. The reaction mixturewas extracted with diethyl ether and combined organic fractions werewashed with brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (silica, 1:1EtOAc:hexanes, 1% methanol:CH₂Cl₂, 10% methanol:CH₂Cl₂ successively) togive the title compound. Mass Spectrum (ESI) m/e M+1 349.1

EXAMPLE 52

3-(1-N-methylamino)-eth-1-yl-1-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole

The title compound was prepared according to procedures described inExample 51. Mass Spectrum (ESI) m/e M+1 363.1.

EXAMPLE 53

3-[3-((2,6-Bis-trifluoromethyl)-phenyl)-phenyl]-1,2,4-triazole-5-carboxamide

The titled compound is prepared using procedures described in Examples19 and 20.

EXAMPLE 54

Mass Spectrum (ESI) m/e M+1 381.

1-35. (canceled)
 36. A compound which is

or a pharmaceutically acceptable salt thereof.
 37. A compound which is

or a pharmaceutically acceptable salt thereof.
 38. A compound which is

or a pharmaceutically acceptable salt thereof.
 39. A compound which is

or a pharmaceutically acceptable salt thereof.
 40. A compound which is

or a pharmaceutically acceptable salt thereof.
 41. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 37, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 42. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 38, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 43. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 39, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 44. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 40, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 45. A method of treatment ofpain comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 37, ora pharmaceutically acceptable salt thereof.
 46. A method of treatment ofpain comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 38, ora pharmaceutically acceptable salt thereof.
 43. A method of treatment ofpain comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 39, ora pharmaceutically acceptable salt thereof.
 44. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 40, or a pharmaceutically acceptable salt thereof.